Ketogenic diet has a positive association with mental and emotional well-being in the general population.

OBJECTIVES: A ketogenic diet reduces pathologic stress and improves mood in neurodegenerative and neurodevelopmental disorders. However, the effects of a ketogenic diet for people from the general population have largely been unexplored. A ketogenic diet is increasingly used for weight loss. Research in healthy individuals primarily focuses on the physical implications of a ketogenic diet. It is important to understand the holistic effects of a ketogenic diet, not only the physiological but also the psychological effects, in non-clinical samples. The aim of this cross-sectional study with multiple cohorts was to investigate the association of a ketogenic diet with different aspects of mental health, including calmness, contentedness, alertness, cognitive and emotional stress, depression, anxiety, and loneliness, in a general healthy population. METHODS: Two online surveys were distributed: cohort 1 used Bond-Lader visual analog scales and Perceived Stress Scale (n = 147) and cohort 2 the Depression Anxiety Stress Scale and revised UCLA Loneliness Scale (n = 276). RESULTS: A ketogenic diet was associated with higher self-reported mental and emotional well-being behaviors, including calmness, contentedness, alertness, cognitive and emotional stress, depression, anxiety, and loneliness, compared with individuals on a non-specific diet in a general population. CONCLUSION: This research found that a ketogenic diet has potential psychological benefits in the general population.

Socioeconomic, Racial, and Insurance Disparities in Clinical Outcomes After Surgery Among Patients With Idiopathic Scoliosis.

BACKGROUND: Socioeconomic status (SES), race, and insurance type correlate with initial curve severity for patients with idiopathic scoliosis, but less is known regarding how these variables impact surgical outcomes. The objectives of this study were to determine the influence of SES, race, and insurance on preoperative appointment attendance, likelihood of obtaining a preoperative second opinion, brace prescription, missed 6 or 12-month postsurgical appointments, incidence of emergency department visits 0 to 90 days after surgery, and major complications within a year of surgery. METHODS: A review of 421 patients diagnosed with idiopathic scoliosis who underwent surgery at a single high-volume pediatric spinal deformity institution between May 2015 and October 2021 was conducted. Area Deprivation Index, a quantitative measure of SES, was collected. Scores were stratified by quartile; higher scores indicated a lower SES. χ 2 tests for correlation were performed to determine whether clinical outcomes were dependent upon Area Deprivation Index, race, or insurance type; P ≤0.05 was significant. RESULTS: The sample was 313 Caucasian (74%), 69 (16%) black, and 39 (9.3%) other patients. More patients had private versus public insurance (80% vs 20%) and were of higher SES. The likelihood of missing preoperative appointments was higher for black patients ( P = 0.037). Those with lower SES missed more postoperative appointments and received less bracing and second opinions ( P = 0.038, P = 0.017, P = 0.008, respectively). Being black and publicly insured correlated with fewer brace prescriptions ( P < 0.001, P = 0.050) and decreased rates of obtaining second opinions ( P = 0.004,  P = 0.001). CONCLUSION: Patients with idiopathic scoliosis surgery who were Caucasian, privately insured, and of higher SES were more likely to seek preoperative second opinions, be prescribed a brace, and attend postoperative appointments. Recognition of the inherent health care disparities prevalent within each pediatric spine surgery referral region is imperative to better inform local and national institutional level programs to educate and assist patients and families most at risk for disparate access to scoliosis care. LEVEL OF EVIDENCE: Level III; retrospective case-control study.

Pricing and reimbursement mechanisms for advanced therapy medicinal products in 20 countries.

Introduction: Advanced Therapy Medicinal Products are a type of therapies that, in some cases, hold great potential for patients without an effective current therapeutic approach but they also present multiple challenges to payers. While there are many theoretical papers on pricing and reimbursement (P&R) options, original empirical research is very scarce. This paper aims to provide a comprehensive international review of regulatory and P&R decisions taken for all ATMPs with centralized European marketing authorization in March 2022. Methods: A survey was distributed in July 2022 to representatives of 46 countries. Results: Responses were received from 20 countries out of 46 (43.5%). 14 countries reimbursed at least one ATMP. Six countries in this survey reimbursed no ATMPs. Conclusion: Access to ATMPs is uneven across the countries included in this study. This arises from regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, for example, through the WHO Regional Office for Europe's Access to Novel Medicines Platform.

Cycle Threshold Values as Indication of Increasing SARS-CoV-2 New Variants, England, 2020-2022.

Early detection of increased infections or new variants of SARS-CoV-2 is critical for public health response. To determine whether cycle threshold (Ct) data from PCR tests for SARS-CoV-2 could serve as an early indicator of epidemic growth, we analyzed daily mean Ct values in England, UK, by gene target and used iterative sequential regression to detect break points in mean Ct values (and positive test counts). To monitor the epidemic in England, we continued those analyses in real time. During September 2020-January 2022, a total of 7,611,153 positive SARS-CoV-2 PCR test results with Ct data were reported. Spike (S) gene target (S+/S-)-specific mean Ct values decreased 6-29 days before positive test counts increased, and S-gene Ct values provided early indication of increasing new variants (Delta and Omicron). Our approach was beneficial in the context of the first waves of the COVID-19 pandemic and can be used to support future infectious disease monitoring.

Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice.

HIV-1 persists indefinitely in people living with HIV (PLWH) on antiretroviral therapy (ART). If ART is stopped, the virus rapidly rebounds from long-lived latently infected cells. Using a humanized mouse model of HIV-1 infection and CD4+ T cells from PLWH on ART, we investigate whether antagonizing host pro-survival proteins can prime latent cells to die and facilitate HIV-1 clearance. Venetoclax, a pro-apoptotic inhibitor of Bcl-2, depletes total and intact HIV-1 DNA in CD4+ T cells from PLWH ex vivo. This venetoclax-sensitive population is enriched for cells with transcriptionally higher levels of pro-apoptotic BH3-only proteins. Furthermore, venetoclax delays viral rebound in a mouse model of persistent HIV-1 infection, and the combination of venetoclax with the Mcl-1 inhibitor S63845 achieves a longer delay in rebound compared with either intervention alone. Thus, selective inhibition of pro-survival proteins can induce death of HIV-1-infected cells that persist on ART, extending time to viral rebound.

Post-treatment evaluation of oral health-related quality of life in head and neck cancer patients after dental implant rehabilitation.

Objectives To assess oral health-related quality of life (OHRQoL) following oral rehabilitation using dental implants in patients treated for head and neck cancer (HNC).Materials and methods Service evaluation: patients who had received dental implants during their oral rehabilitation were invited to take part (n = 81). In total, 37 patients completed questionnaires and underwent a structured interview regarding OHRQoL after rehabilitation. Analysis was by descriptive statistics for questionnaire and thematic analysis of interview.Results Rehabilitation types were 17 fixed implant prostheses, 12 removable implant prostheses and 8 combination. Functional problems relating to HNC treatment had a significant effect on OHRQoL and persisted after rehabilitation. Removable implant prostheses had more problems associated than fixed. At interview, patients described: functional and emotional benefits of oral rehabilitation involving implants; ease of keeping implants clean; variations in ability of primary care dentists to maintain rehabilitation; thankfulness to have received treatment; long duration of rehabilitation; and problems encountered while undergoing rehabilitation.Conclusions HNC treatment results in functional and emotional difficulties, which has a significant impact on OHRQoL. Use of dental implants in fixed or removable oral rehabilitation can result in good OHRQoL as assessed by patients at treatment completion, although some functional difficulties often remain.

A novel chlorhexidine-hexametaphosphate coating for titanium with antibiofilm efficacy and stem cell cytocompatibility.

Dental implants are an increasingly popular way to replace missing teeth. Whilst implant survival rates are high, a small number fail soon after placement, with various factors, including bacterial contamination, capable of disrupting osseointegration. This work describes the development of chlorhexidine-hexametaphosphate coatings for titanium that hydrolyse to release the antiseptic agent chlorhexidine. The aim was to develop a coating for titanium that released sufficient chlorhexidine to prevent biofilm formation, whilst simultaneously maintaining cytocompatibility with cells involved in osseointegration. The coatings were characterised with respect to physical properties, after which antibiofilm efficacy was investigated using a multispecies biofilm model, and cytocompatibility determined using human mesenchymal stem cells. The coatings exhibited similar physicochemical properties to some implant surfaces in clinical use, and significantly reduced formation of multispecies biofilm biomass up to 72 h. One coating had superior cytocompatibility, with mesenchymal stem cells able to perform normal functions and commence osteoblastic differentiation, although at a slower rate than those grown on uncoated titanium. With further refinement, these coatings may have application in the prevention of bacterial contamination of dental implants at the time of surgery. This could aid a reduction in rates of early implant failure.

Corrigendum: Variations in the Consumption of Antimicrobial Medicines in the European Region, 2014-2018: Findings and Implications From ESAC-Net and WHO Europe.

[This corrects the article DOI: 10.3389/fphar.2021.639207.].

European collaborations on medicine and vaccine procurement.

To ensure equitable access to medicines and vaccines, organizational efforts and purchase volumes have been pooled in joint procurements and negotiations for decades in some regions of the world, as well as globally through supranational procurement mechanisms. In Europe, countries started to collaborate on procurement and negotiations recently when it became increasingly difficult to ensure access to high-priced medicines, even in high-income countries. Two European country collaborations (the Nordic Pharmaceutical Forum and the Baltic Procurement Initiative) have successfully concluded at least one joint tender process for medicines and vaccines and the Beneluxa Initiative has concluded its first successful joint price negotiation. This article describes the experiences of these country collaborations. Challenges observed included: legal barriers; institutional and organizational differences between health-care systems in member countries; and the risk that suppliers will be reluctant to cooperate with country collaborations. Although these collaborations helped improve access to medicines and vaccines for the countries involved, in situations such as a global health crisis, larger-scale, more-inclusive initiatives are needed. In the current coronavirus disease 2019 (COVID-19) pandemic, COVID-19 Vaccines Global Access (COVAX) initiative established a global procurement mechanism to ensure the equitable distribution of COVID-19 vaccines globally. Despite differences in organization and scale, the European country collaborations and COVAX have some similarities: (i) their success depends on the increased purchasing power associated with pooled order volumes; (ii) expert knowledge and previous procurement experience is pooled; (iii) they perform other collaborative activities that go beyond procurement alone; and (iv) they actively involve external partners and stakeholders.

Depuis des décennies, certaines régions du monde ont uni leurs efforts pour s'organiser, négocier et effectuer des achats groupés de grandes quantités afin d'assurer un accès équitable aux médicaments et vaccins. Des mécanismes d'acquisition supranationaux ont fait de même à l'échelle planétaire. En Europe, des États ont récemment commencé à collaborer en matière d'achat et de négociation lorsqu'il est devenu de plus en plus difficile de garantir l'accès à des médicaments coûteux, y compris dans les pays à haut revenu. Deux collaborations entre pays européens (le Forum pharmaceutique nordique et l'Initiative d'acquisition de la Baltique) ont mené à bien au moins un processus d'offre conjoint pour des médicaments et vaccins, tandis que l'Initiative Beneluxa a conclu sa première négociation tarifaire conjointe. Cet article décrit les expériences liées à ces collaborations entre nations. Plusieurs défis se sont posés, notamment des obstacles juridiques; des différences institutionnelles et organisationnelles entre les systèmes de santé des États membres; et enfin, le risque que les fournisseurs soient peu enclins à accepter ces collaborations entre pays. Bien que ces collaborations aient amélioré l'accès aux médicaments et vaccins pour les pays impliqués, des initiatives plus globales et à plus grande échelle sont nécessaires dans des situations telles qu'une crise sanitaire mondiale. Durant l'actuelle pandémie de maladie à coronavirus 2019 (COVID-19), l'initiative COVAX (COVID-19 Vaccines Global Access) a abouti à un dispositif d'approvisionnement mondial pour veiller à distribuer équitablement des vaccins contre la COVID-19 dans le monde. Malgré des variations d'organisation et d'échelle, les collaborations entre États européens partagent des similitudes avec le COVAX: (i) le succès de ces deux démarches dépend d'un accroissement du pouvoir d'achat combiné à des volumes de commande groupés; (ii) elles mettent en commun les connaissances approfondies et expériences passées; (iii) elles mènent d'autres activités collectives qui dépassent le simple cadre de l'acquisition; et enfin, (iv) elles impliquent activement une série d'intervenants et de partenaires externes.

Para garantizar un acceso equitativo a los medicamentos y las vacunas, los esfuerzos organizativos y los volúmenes de compra se han unido en adquisiciones y negociaciones conjuntas durante décadas en algunas regiones del mundo, así como a nivel mundial a través de mecanismos de adquisición supranacionales. En Europa, los países empezaron a colaborar en las adquisiciones y negociaciones recientemente, cuando se hizo cada vez más difícil garantizar el acceso a los medicamentos con precios altos, incluso en los países de renta alta. Dos colaboraciones de países europeos (el Foro Farmacéutico Nórdico y la Iniciativa de Adquisición del Báltico) han concluido con éxito al menos un proceso de licitación conjunta de medicamentos y vacunas, y la Iniciativa Beneluxa ha concluido con éxito su primera negociación conjunta de precios. Este artículo describe las experiencias de estas colaboraciones entre países. Entre los retos observados se encuentran: las barreras legales, las diferencias institucionales y organizativas entre los sistemas sanitarios de los países miembros y el riesgo de que los proveedores se muestren reacios a cooperar con las colaboraciones entre países. Aunque estas colaboraciones ayudaron a mejorar el acceso a los medicamentos y las vacunas para los países implicados, en situaciones como una crisis sanitaria mundial, se necesitan iniciativas a mayor escala y más inclusivas. En la actual pandemia de la enfermedad por coronavirus (COVID-19), la iniciativa Acceso global a las vacunas de la COVID-19 (COVAX, por sus siglas en inglés) estableció un mecanismo de adquisición mundial para garantizar la distribución equitativa de las vacunas contra la COVID-19 en todo el mundo. A pesar de las diferencias de organización y escala, las colaboraciones de los países europeos y COVAX tienen algunas similitudes: i) su éxito depende del mayor poder adquisitivo asociado a los volúmenes de pedidos mancomunados; ii) se ponen en común los conocimientos de los expertos y la experiencia previa en materia de adquisiciones; iii) realizan otras actividades de colaboración que van más allá de la mera adquisición; e iv) implican activamente a socios y partes interesadas externas.

Variations in the Consumption of Antimicrobial Medicines in the European Region, 2014-2018: Findings and Implications from ESAC-Net and WHO Europe.

Background: Surveillance of antimicrobial consumption (AMC) is important to address inappropriate use. AMC data for countries in the European Union (EU) and European Economic Area (EEA) and Eastern European and Central Asian countries were compared to provide future guidance. Methods: Analyses of 2014-2018 data from 30 EU/EEA countries of the European Surveillance of Antibiotic Consumption network (ESAC-Net) and 15 countries of the WHO Regional Office for Europe (WHO Europe) AMC Network were conducted using the Anatomical Therapeutic Chemical (ATC) classification and Defined Daily Dose (DDD) methodology. Total consumption (DDD per 1000 inhabitants per day) of antibacterials for systemic use (ATC group J01), relative use (percentages), trends over time, alignment with the WHO Access, Watch, Reserve (AWaRe) classification, concordance with the WHO global indicator (60% of total consumption should be Access agents), and composition of the drug utilization 75% (DU75%) were calculated. Findings: In 2018, total consumption of antibacterials for systemic use (ATC J01) ranged from 8.9 to 34.1 DDD per 1000 inhabitants per day (population-weighted mean for ESAC-Net 20.0, WHO Europe AMC Network 19.6, ESAC-Net Study Group, and WHO Europe AMC Network Study Group). ESAC-Net countries consumed more penicillins (J01C; 8.7 versus 6.3 DDD per 1000 inhabitants per day), more tetracyclines (J01A; 2.2 versus 1.2), less cephalosporins (J01D; 2.3 versus 3.8) and less quinolones (J01M; 1.7 versus 3.4) than WHO Europe AMC Network countries. Between 2014 and 2018, there were statistically significant reductions in total consumption in eight ESAC-Net countries. In 2018, the relative population-weighted mean consumption of Access agents was 57.9% for ESAC-Net and 47.4% for the WHO Europe AMC Network. For each year during 2014-2018, 14 ESAC-Net and one WHO Europe AMC Network countries met the WHO global monitoring target of 60% of total consumption being Access agents. DU75% analyses showed differences in the choices of agents in the two networks. Interpretation: Although total consumption of antibacterials for systemic use was similar in the two networks, the composition of agents varied substantially. The greater consumption of Watch group agents in WHO Europe AMC Network countries suggests opportunities for improved prescribing. Significant decreases in consumption in several ESAC-Net countries illustrate the value of sustained actions to address antimicrobial resistance.

European List of Essential Medicines for Medical Education: a protocol for a modified Delphi study.

INTRODUCTION: Junior doctors are responsible for a substantial number of prescribing errors, and final-year medical students lack sufficient prescribing knowledge and skills just before they graduate. Various national and international projects have been initiated to reform the teaching of clinical pharmacology and therapeutics (CP&T) during undergraduate medical training. However, there is as yet no list of commonly prescribed and available medicines that European doctors should be able to independently prescribe safely and effectively without direct supervision. Such a list could form the basis for a European Prescribing Exam and would harmonise European CP&T education. Therefore, the aim of this study is to reach consensus on a list of widely prescribed medicines, available in most European countries, that European junior doctors should be able to independently prescribe safely and effectively without direct supervision: the European List of Essential Medicines for Medical Education. METHODS AND ANALYSIS: This modified Delphi study will recruit European CP&T teachers (expert group). Two Delphi rounds will be carried out to enable a list to be drawn up of medicines that are available in ≥80% of European countries, which are considered standard prescribing practice, and which junior doctors should be able to prescribe safely and effectively without supervision. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Review Committee of VU University Medical Center (no. 2020.335) and by the Ethical Review Board of the Netherlands Association for Medical Education (approved project no. NVMO-ERB 2020.4.8). The European List of Essential Medicines for Medical Education will be presented at national and international conferences and will be submitted to international peer-reviewed journals. It will also be used to develop and implement the European Prescribing Exam.

Generating comparative evidence on new drugs and devices before approval.

Fewer than half of new drugs have data on their comparative benefits and harms against existing treatment options at the time of regulatory approval in Europe and the USA. Even when active-comparator trials exist, they might not produce meaningful data to inform decisions in clinical practice and health policy. The uncertainty associated with the paucity of well designed active-comparator trials has been compounded by legal and regulatory changes in Europe and the USA that have created a complex mix of expedited programmes aimed at facilitating faster access to new drugs. Comparative evidence generation is even sparser for medical devices. Some have argued that the current process for regulatory approval needs to generate more evidence that is useful for patients, clinicians, and payers in health-care systems. We propose a set of five key principles relevant to the European Medicines Agency, European medical device regulatory agencies, US Food and Drug Administration, as well as payers, that we believe will provide the necessary incentives for pharmaceutical and device companies to generate comparative data on drugs and devices and assure timely availability of evidence that is useful for decision making. First, labelling should routinely inform patients and clinicians whether comparative data exist on new products. Second, regulators should be more selective in their use of programmes that facilitate drug and device approvals on the basis of incomplete benefit and harm data. Third, regulators should encourage the conduct of randomised trials with active comparators. Fourth, regulators should use prospectively designed network meta-analyses based on existing and future randomised trials. Last, payers should use their policy levers and negotiating power to incentivise the generation of comparative evidence on new and existing drugs and devices, for example, by explicitly considering proven added benefit in pricing and payment decisions.

Managed Entry Agreements for Pharmaceuticals in the Context of Adaptive Pathways in Europe.

As per the EMA definition, adaptive pathways is a scientific concept for the development of medicines which seeks to facilitate patient access to promising medicines addressing high unmet need through a prospectively planned approach in a sustainable way. This review reports the findings of activities undertaken by the ADAPT-SMART consortium to identify enablers and explore the suitability of managed entry agreements for adaptive pathways products in Europe. We found that during 2006-2016 outcomes-based managed entry agreements were not commonly used for products with a conditional marketing authorization or authorized under exceptional circumstances. The barriers and enablers to develop workable managed entry agreements models for adaptive pathways products were discussed through interviews and a multi-stakeholder workshop with a number of recommendations made in this paper.

DECISION-COMPONENTS OF NICE'S TECHNOLOGY APPRAISALS ASSESSMENT FRAMEWORK.

OBJECTIVES: Value assessment frameworks have gained prominence recently in the context of U.S. healthcare. Such frameworks set out a series of factors that are considered in funding decisions. The UK's National Institute of Health and Care Excellence (NICE) is an established health technology assessment (HTA) agency. We present a novel application of text analysis that characterizes NICE's Technology Appraisals in the context of the newer assessment frameworks and present the results in a visual way. METHODS: A total of 243 documents of NICE's medicines guidance from 2007 to 2016 were analyzed. Text analysis was used to identify a hierarchical set of decision factors considered in the assessments. The frequency of decision factors stated in the documents was determined and their association with terms related to uncertainty. The results were incorporated into visual representations of hierarchical factors. RESULTS: We identified 125 decision factors, and hierarchically grouped these into eight domains: Clinical Effectiveness, Cost Effectiveness, Condition, Current Practice, Clinical Need, New Treatment, Studies, and Other Factors. Textual analysis showed all domains appeared consistently in the guidance documents. Many factors were commonly associated with terms relating to uncertainty. A series of visual representations was created. CONCLUSIONS: This study reveals the complexity and consistency of NICE's decision-making processes and demonstrates that cost effectiveness is not the only decision-criteria. The study highlights the importance of processes and methodology that can take both quantitative and qualitative information into account. Visualizations can help effectively communicate this complex information during the decision-making process and subsequently to stakeholders.